1. Field of the Invention
This invention is in the field of methods and pharmaceutical compositions for treating or preventing Multiple Sclerosis, Encephalitis, and other autoimmune diseases that are associated with an abnormal increase in the number of activated T-cells.
2. Description of the Related Art
Multiple sclerosis (MS) is a severe, chronic disabling disease that affects approximately 1 out of every 1,600 people. The majority of the affected individuals develop symptoms as young adults between 20 and 40 years of age, with roughly 60% of the cases occurring in women. The disease is characterized by neuron deterioration in the central nervous system (CNS) with the associated loss of the insulating myelin sheath from around the axons of the nerve cells, referred to as demyelination. The disease presents itself in the white matter of the brain and spinal cord as a number of sclerotic lesions or plaques (Prineas (1985) Demyelinating Diseases, Elsvevier: Amsterdam; Raine (1983) Multiple Sclerosis, Williams and Wilkins: Baltimore; Raine et al. (1988) J. Neuroimmunol. 20:189-201; and Martin (1997) J. Neural Transmission (Suppl) 49:53-67). The characteristic MS lesion is inflamed, exhibits axonal demyelination, axonal degeneration, and is found around small venules. These characteristics typically evolve early in plaque development and are hypothesized to occur as a result of a breakdown in the blood-brain barrier (BBB). As a consequence of BBB breakdown, infiltrates consisting of various lymphocytes and macrophages enter the brain or spinal cord. This inflammatory infiltrate ultimately leads to axonal degeneration and scar tissue formation, and in many instances, is associated with incomplete remyelination (Martin (1997) J. Neural Transmission (Suppl) 49:53-67). Further, it is hypothesized that this apparent immunologic attack targets not only the myelin sheath, but also the oligodendrocytes imperative to CNS myelin production. As a result, not only is the nerve-insulating myelin damaged, but the ability of oligodendroglial cells to repair damaged myelin is seriously compromised (Scientific American 269 (1993):106-114). Development of multiple areas of scar tissue (sclerosis) along the covering of the nerve cells slows or blocks the transmission of nerve impulses in the affected area, resulting in the development of the symptoms characteristic of MS. These symptoms include pain and tingling in the arms and legs; localized and generalized numbness, muscle spasm and weakness; difficulty with balance when standing or walking; difficulty with speech and swallowing; cognitive deficits; fatigue; and bowel and bladder dysfunction.
Approximately half of the people with this disease suffer from relapsing-remitting MS. In these cases, the afflicted individual experiences repeated unpredictable attacks, due to episodes of inflammation, axonal demyelination, axonal degeneration, and development of glial scar tissue. These attacks are separated by periods of remission, during which the symptoms stabilize or diminish. Acute neurological deficits occur with each attack, and in many cases, the accumulation of residual deficits as a result of these attacks eventually leads to worsening disability and impairment in quality of life. Approximately 30-40% of the afflicted population have chronic progressive MS (either primary or secondary) in which neurological deterioration occurs in the absence of clinically apparent attacks. Recently, immunomodulatory therapy with interferon-beta (IFN-beta) has proven to be successful in reducing the severity of the underlying disease in patients with relapsing-remitting MS. FDA-approved IFN-beta therapies for the treatment of relapsing-remitting MS in the United States include interferon beta-1a (marketed as Avonex®, available from Biogen, Inc.) and interferon-beta-1b (marketed as Betaseron®, available from Chiron Corporation). Both of these therapeutic agents are partially effective in reducing the frequency and severity of relapses, slowing the rate of disease progression, or reducing the degree of brain inflammation as measured by a variety of magnetic resonance imaging (MRI) techniques.
MS is considered to be a T cell-mediated autoimmune disease of the brain and spinal cord [Traugott et al. 1983; Vizler et al. 1999]. The failed apoptosis of auto-reactive T cells has been implicated in MS pathogenesis. While there appears to be a localized CNS immune response, peripheral immune cell abnormalities appear to correlate with central disease activity [Hafler and Weiner 1989] and may precede MRI activity. Apoptosis is an important mechanism in immune system regulation, responsible for elimination of autoreactive T-lymphocytes (T cells), B-lymphocytes (B cells) and monocytes from the circulation and prevention of their entry into the CNS [Mahoney and Rosen 2005; Todaro et al. 2004]. It has been hypothesized that a genetic predisposition exists in MS patients whereby a failure of autoreactive T cells and B cells as well as activated macrophages to undergo apoptosis contributes to the pathogenesis of MS [Bernard and Derosbo 1992; Pender 1998; Pender and Rist 2001].
Prescribing decisions seem to be driven by evidence-based medicine and a recent report by the American Association of Neurologists (Goodin D S et al; Neurology Jan. 22, 2002; 58(2):169-78) is a key document. The consensus amongst many neurologists is that early, aggressive therapy with beta-interferons was desirable in increasing the time to first relapse and limiting the overall disease load, although it was recognized that there was no evidence that this approach showed long-term benefit on EDSS score (a measure of disease-related disability). There is currently no satisfactory diagnostic marker for multiple sclerosis. There is therefore a need for new diagnostic methods and for new disease-modifying therapies for MS.